Amino amides, peptides and peptidomimetics

ABSTRACT

Synthetic methods and compounds involving amino amides, peptides and peptidomimetics. Amino amide derivatives are prepared via the one-step three-component reaction of a glyoxamide, an amine, and an organoboron derivative. Conversion of the product to another glyoxamide intermediate allows the iterative use of this chemistry for the synthesis of peptides and peptidomimetics.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/369,542, filed on Apr. 1, 2002, which is incorporated herein byreference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

The U.S. Government may have certain rights in this invention pursuantto Grant No. GM45970 awarded by the National Institutes of Health.

BACKGROUND

The present application relates to amino amides, peptides andpeptidomimetics, and methods for preparing such compounds.

The unique roles of various peptides, including their function asextra-cellular messengers, hormones, neurotransmitters neuromodulators,and immune defense modulators, is well established. Consequently, theuse of peptides or amino amides containing natural and unnatural aminoacid units against many therapeutic targets is of continued interest.Numerous methods have been developed for the synthesis of amino amidesor peptides both in solution and on a solid support (Bodanszky, M.Principle of Peptide Synthesis, 2nd Edition, Springer-Verlag, Berlin,1993; Guillier, F.; Orain, D.; Bradley, M. Chem. Rev., 100:2091;100:2091; 2000; Humphrey, J. M.; Chamberlin, A. R. Chem. Rev., 97:2243,1997).

Due to difficulties resulting from the limited selectivity, stability,delivery and bioavailability of certain peptides, the design andsynthesis of peptidomimetic molecules continues to be at the forefrontof drug design and discovery and many peptidomimetic frameworks andmethods for their synthesis have been developed (Babine, R. E.; Bender,S. L., Chem. Rev., 97:1359, 1997; Hanessian, S.; et al., Tetrahedron,53:12789, 1997; Fletcher, M. D.; Cambell, M. C., Chem. Rev., 98:763,1998).

Traditional peptide synthesis in both solution phase and solid phaseinvolves the stepwise or iterative use of the following sixtransformations: (a) synthesis of amino acid units; (b) monoprotectionof certain amino acid units at their N-terminus; (c) monoprotection ofcertain amino acid units at their C-terminus; (d) coupling of anN-protected and a C-protected amino acid unit via amide bond formation;(e) removal of the protecting group from the N-terminus; and (f) removalof the protective group from the C-terminus. A number of unconventionalapproaches to the synthesis of peptides have also been developed,including the use of the Ugi four-component condensation reaction ofacids, aldehydes, isocyanides and amines (Waki, M.; Meienhofer, J. J.Am. Chem. Soc., 99:6075, 1977; Hoyng, C. F.; Patel, A. D. TetrahedronLett., 21:4795, 1980).

Among the drawbacks of the traditional approaches to peptides andpeptidomimetics is the large number of required reaction steps and thedifficulties in incorporating certain unnatural amino acid side chains,such as alkenyl, alkynyl, allenyl, aryl and heteroaryl groups.

SUMMARY OF THE INVENTION

The present invention provides synthetic methods and compounds,involving amino amides, peptides and peptidomimetics. Amino amidederivatives are prepared via the one-step three-component reaction of aglyoxamide, an amine, and an organoboron derivative. Conversion of theproduct to another glyoxamide intermediate allows the iterative use ofthis chemistry for the synthesis of peptides and peptidomimetics.

In one aspect of the invention, which is outlined in Scheme 1, a peptideis prepared via the sequential use of the following three steps. Step A:conversion of an amine 1 to a glyoxamide 2; Step B: one-stepthree-component reaction between glyoxamide 2, an amine 3 andorganoboron derivative 4 to form amino amide 5; and Step C: removal ofat least one amine substituent from amino amide 5 to form amino amide 6.Iterative use of these three steps converts amino amide 6 to a dipeptide11, while further iterations or conventional couplings with compounds 6or 11 lead to oligopeptides or polypeptides.

In another aspect, a conceptually related approach is used for thesynthesis of peptidomimetics having one or more peptide bonds (N—C═O)replaced or switched by amine bonds. As outlined in Scheme 1, suchpeptidomimetics can be produced by using an amino amide intermediate(e.g., 6 or 11, or the starting amine derivative 1) as the aminecomponent in the three-component process. For example, as shown inScheme 1, reaction of amino amide 6 with and organoboron derivative 12and glyoxamide 13 gives the peptidomimetic system 14. Alternatively, byusing a glyoxamide intermediate (e.g., 2 or 7) as the carbonyl componentin combination with an amino amide (or amino acid) as the aminecomponent in the three-component process, a different type ofpeptidomimetic system is produced. For example, as shown in Scheme 1,reaction of 7 with amino amide 16 and organoboron derivative 15 givesthe peptidomimetic derivative 17. This process can be used iterativelyto attach additional amino acid units or it can be combined with apeptide-producing sequence to generate a large variety of peptidomimeticproducts. The reactions of the present invention can be performed insolution or in the solid phase by incorporating one of the peptide orpeptidomimetic substituents on a suitable solid support.

One step in the reactions of the present invention (Step A) involves theconversion of an amine, amino amide or peptide derivative to thecorresponding glyoxamide. There are several known methods that can beused for the synthesis of glyoxamides (König, S.; Lohiberger, S.; Ugi,I. Synthesis, 1233, 1993; Marx, M. A. et al J. Am. Chem. Soc., 119:6153,1997; Blaser, E. et al Eur. J. Org. Chem., 329, 1999), including theSwern oxidation of glycolamides, the ozonolysis of alkenylamides, andcleavage of diol amides. More substituted ketoamide derivatives can begenerated similarly or using other known methods, and can be used in theplace of glyoxamides, leading to even more substituted products.

Overall this approach does not require the pre-synthesis andmono-protection of the amino acid units, relying instead on the assemblyof the amino acid moieties directly on the peptide or peptidomimeticframework. In this manner, a smaller number of overall steps isrequired, particularly if the peptide involves unnatural amino acidunits.

In general, in one aspect, the present invention features a method ofpreparing an amino amide of formula 5 or formula 6. An amine derivative1 is converted to a glyoxamide intermediate 2 which is reacted with anamine 3 and an organoboron derivative 4 to form amino amide 5. The useof a primary amine 3 having Ra=R⁴ and Rb=H gives amino amide 6.Alternatively, compound 6 is produced from compound 5 via the removal ofone or both substituents Ra and Rb, followed by the incorporation of R⁴

wherein:

-   -   R¹, R² and R⁴ are independently selected from a group consisting        of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl,        sulfonyl, amino, alkylamino, dialkylamino, acylamino,        sulfonylamino, and alkoxy, provided that R¹ and R² can also be        connected together forming a ring;    -   Rw can be hydrogen, alkyl, aryl or heteroaryl;    -   R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, or        allenyl;    -   Ra and Rb are independently selected from a group consisting of        hydrogen, alkyl, allyl, benzyl, aryl, heteroaryl, acyl,        sulfonyl, amino, alkylamino, dialkylamino, acylamino,        sulfonylamino, and alkoxy, provided that Ra and Rb can also be        joined together forming a ring; and    -   X and Y are independently selected from a group consisting of        hydroxy, alkoxy, aryloxy, amino, alkylamino, and dialkylamino,        provided that X and Y can also be joined together forming a        ring.

In particular embodiments, R¹, R², R³, Ra, Rb, Rw, X or Y can also beconnected to a polymeric chain or other solid phase material.

In another aspect, the present invention features a method of preparinga peptide of formula 10 or of formula 11. An amino amide derivative 6 isconverted to a glyoxamide intermediate 7 which is reacted with an amine8 and an organoboron derivative 9 to form dipeptide 10. The use of aprimary amine 8 having Rc=R⁶ and Rd=H gives peptide 11. Alternatively,compound 11 is produced from compound 10 via the removal of one or bothsubstituents Rc and Rd, followed by the incorporation of R⁶

wherein:

-   -   R¹, R², R⁴ and R⁶ are independently selected from a group        consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl,        acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino,        sulfonylamino, and alkoxy, provided that two or more of R¹, R²,        R⁴ and R⁶ can also be connected together forming one or more        rings;    -   Rw is hydrogen, alkyl, aryl or heteroaryl.

R³ and R⁵ are independently selected from a group consisting of alkyl,aryl, heteroaryl, allyl, alkenyl, alkynyl, and allenyl;

-   -   Rc and Rd are independently selected from a group consisting of        hydrogen, alkyl, allyl, benzyl, aryl, heteroaryl, acyl,        sulfonyl, amino, alkylamino, dialkylamino, acylamino,        sulfonylamino, and alkoxy, provided that Rc and Rd can also be        joined together forming a ring; and    -   X and Y are independently selected from a group consisting of        hydroxy, alkoxy, aryloxy, amino, alkylamino, and dialkylamino,        provided that X and Y can also be joined together forming a        ring.

In particular embodiments, R¹, R², R³, R⁴, R⁵, Rc, Rd, X or Y can beconnected to a polymeric chain or other solid phase material.

In general, in another aspect, the present invention features a methodof preparing a peptidomimetic of formula 14. An amino amide derivative 6is reacted with a 1,2-dicarbonyl compound 13 and an organoboronderivative 12 to form peptidomimetic 14

wherein:

-   -   R¹, R², and R⁴ are independently selected from a group        consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl,        acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino,        sulfonylamino, and alkoxy, provided that two or more of R¹, R²,        R³ and R⁴ can also be connected together forming one or more        rings;    -   Rw is hydrogen, alkyl, aryl or heteroaryl.    -   R⁸ is hydrogen, alkyl, alkenyl, aryl, heteroaryl, amino,        alkylamino, dialkylamino, hydroxyamino, alkoxyamino, hydroxyl,        alkoxy, aryloxy or heteroaryloxy;    -   R³ and R⁷ are independently selected from a group consisting of        alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, and allenyl;        and    -   X and Y are independently selected from a group consisting of        hydroxy, alkoxy, aryloxy, amino, alkylamino, and dialkylamino,        provided that X and Y can also be joined together forming a        ring.

In particular embodiments, R¹, R², R³, R⁴, R⁷, R⁸, X or Y can also beconnected to a polymeric chain or other solid phase material.

In general, in another aspect, the present invention features a methodof preparing a peptidomimetic of formula 17. An amino amide derivative 6is converted to a glyoxamide intermediate 7, which is reacted with and aorganoboron derivative 15 and an amino carbonyl derivative 16 to formpeptidomimetic 17

wherein:

-   -   R¹, R², R⁴, and R¹⁰ are independently selected from a group        consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl,        acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino,        sulfonylamino, and alkoxy, provided that two or more of R¹, R²,        R³ and R⁴ can also be connected together forming one or more        rings, and that two or more of R¹⁰, R¹¹ and R¹² can also be        connected together forming one or more rings;    -   Rw is hydrogen, alkyl, aryl or heteroaryl.    -   R³, R⁹ and R¹¹ are independently selected from a group        consisting of alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl,        and allenyl;    -   R¹² is hydrogen, alkyl, alkenyl, aryl, heteroaryl, amino,        alkylamino, dialkylamino, hydroxyamino, alkoxyamino, hydroxyl,        alkoxy, aryloxy or heteroaryloxy; and    -   X and Y are independently selected from a group consisting of        hydroxy, alkoxy, aryloxy, amino, alkylamino, or dialkylamino,        provided that X and Y can also be joined together forming a        ring.

In particular embodiments, R¹, R², R³, R⁴, R⁹, R¹⁰, R¹¹, R¹², Rw, X or Ycan also be connected to a polymeric chain or other solid phasematerial.

Particular embodiments of the invention can provide one or more of thefollowing advantages. The synthetic methods of the invention provide anefficient and practical route to novel structures that are not readilyavailable by other methods. The methods are highly versatile, allowing ahigh degree of structural variation in the reacting components. Themethods allow the formation of complex amino amides peptides andpeptidomimetics from several readily available building blocks. Forthese reasons, the methods are readily applicable to solid or liquidphase combinatorial synthesis.

The reactions with the organoboron derivatives can be carried out inwater or aqueous solvents at ambient temperature, allowing the synthesisof highly hydrophilic products without the need for unnecessaryprotection-deprotection steps. The reactions can be carried out withoutusing toxic, hazardous or corrosive materials, such as cyanides, strongacids, strong bases, organotin, organocopper or other highly reactiveorganometallic compounds. The reactions do not require an inertatmosphere, and can be done in the air. In particular, the organoboronicacids used in some embodiments are often crystalline, easy to prepareand easy to handle compounds that are stable in air and water. They arealso non toxic and non hazardous.

By using the synthetic methods of the present invention, the aminoamides, peptides and peptidomimetics can be prepared using a smallernumber of synthetic steps than most existing methods. Starting materialsused in the reactions are generally either commercially available or canbe readily prepared from commercially available reagents by a procedureinvolving one or more steps.

The stereochemical control of the reactions can be accomplished not onlywith the use of chiral amine and carbonyl components but also withchiral organoboron derivatives. Boron-based auxiliaries can be easilyintroduced and can be efficiently recycled after the reaction, thusmaking this method especially attractive for large scale applications.Due to the facile synthesis of alkenyl and aryl boron derivatives, whichproceed with complete control of geometry or positional isomerism,isomerically pure products can be obtained.

The details of one or more embodiments of the invention are set forth inthe description below. Unless otherwise defined, all technical andscientific terms used herein have the meaning commonly understood by oneof ordinary skill in the art to which this invention belongs. Allpublications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety. Incase of conflict, the present specification, including definitions, willcontrol. Other features and advantages of the invention will becomeapparent from the description and the claims.

DETAILED DESCRIPTION

Definitions:

An organoboron derivative, as defined herein, comprises a compoundhaving a boron atom connected to at least one alkyl, allyl, alkenyl,aryl, allenyl or alkynyl group.

As used in this specification, alkyl groups can includestraight-chained, branched and cyclic alkyl radicals containing up toabout 20 carbons. Suitable alkyl groups may be saturated or unsaturated.Further, an alkyl may also be substituted one or more times on one ormore carbons with substituents selected from the group consisting ofC1-C6 alkyl, C3-C6 heterocycle, aryl, halo, hydroxy, amino, alkoxy andsulfonyl. Additionally, an alkyl group may contain up to 10 heteroatomsor heteroatom substituents. Suitable heteroatoms include nitrogen,oxygen, sulfur and phosphorous.

As used in this specification, aryl groups are aryl radicals which maycontain up to 10 heteroatoms. An aryl group may also be optionallysubstituted one or more times with an aryl group or a lower alkyl groupand it may be also fused to other aryl or cycloalkyl rings. Suitablearyl groups include, for example, phenyl, naphthyl, tolyl, imidazolyl,pyridyl, pyrroyl, thienyl, pyrimidyl, thiazolyl and furyl groups.

As used in this specification, a ring is defined as having up to 20atoms that may include one or more nitrogen, oxygen, sulfur orphosphorous atoms, provided that the ring can have one or moresubstituents selected from the group consisting of hydrogen, alkyl,allyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro,hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino,acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio, acylthio,alkylsulfonate, arylsulfonate, phosphoryl, and sulfonyl, and furtherprovided that the ring may also contain one or more fused rings,including carbocyclic, heterocyclic, aryl, or heteroaryl rings.

General Description:

According to one aspect of the present invention, an amino amide, apeptide or a peptidomimetic (e.g., 5) is prepared by means of thesequential or iterative combination of three steps. Step A involves theconversion of an amine, amino amide or peptide derivative (e.g., 1) to aglyoxamide (e.g., 2). Step B involves the one-step three componentreaction among a glyoxamide (e.g., 2), an amine or amino amide (e.g., 3)and an organoboron derivative (e.g., 4). Step C involves the removal ofone or both substituents of the amine moiety of amino amide product (orpeptide or peptidomimetic) to give a new product (e.g., 6) directly orafter the incorporation of an alternative amine substituent. Iterativeapplication of the same steps extends the peptide chain, while the useof alternative components for the three-component step B leads topeptidomimetics.

Amino Amides:

In one aspect, the methods of the invention can be used for thesynthesis of amino amides of formula 5 or formula 6.

In these methods, R¹, R² and R⁴ are independently selected from a groupconsisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl,sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, andalkoxy. In some embodiments, R¹ and R² can be connected together forminga ring. R³ can be alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, orallenyl. Rw can be hydrogen, alkyl, aryl or heteroaryl. Ra and Rb areindependently selected from a group consisting of hydrogen, alkyl,allyl, benzyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino,dialkylamino, acylamino, sulfonylamino, and alkoxy. In some embodiments,Ra and Rb can be joined together forming a ring. X and Y areindependently selected from a group consisting of hydroxy, alkoxy,aryloxy, amino, alkylamino, and dialkylamino. In some embodiments, X andY can be joined together forming a ring. In some embodiments, R¹, R²,R³, Ra, Rb, Rw, X or Y can also be connected to a polymeric chain orother solid phase material.

Step A, the conversion of an amine 1 to a glyoxamide derivative 2, canbe done in a variety of ways. For example, as shown in Scheme 2, thistransformation can be done by converting the amine 1 to an alkenylamide18, via an acylation reaction with a suitable derivative of thecorresponding alkenyl carboxylic acid, followed by ozonolysis.Alternatively, acylation of 1 with a diol acid can form diol amide 19,which can be subjected to periodate cleavage to form glyoxamide 2. Thisvariation has the advantage that it avoids ozonolysis, making itsuitable for solid phase synthesis and for molecules containing C═Cbonds. Another approach for converting 1 to 2 involves the formation ofa functionalized glycolamide 20 (e.g., W=Br, OH), followed by oxidationto form 1. A typical conversion of an amine to a glyoxamide is theconversion of 21 to 24 via 22 or the tartaric acid derivative 23 (Scheme2).

These methods for glyoxamide synthesis are also applicable for similartransformations on amino amides or peptides. More substituted ketoamidederivatives can be generated similarly by using alpha-substitutedalkenyl amides or alpha-substituted diolamides, or using other knownmethods, and can be used in the place of glyoxamides, leading to evenmore substituted products.

Step B involves the one-step three-component reaction among theglyoxamide 2 (which can be used directly from Step A without furtherpurification), an amine 3 and a boronic acid or related organoboronderivative 4. A related one-step three-component transformation isdiscussed in more detail in U.S. Pat. No. 6,232,467, which isincorporated by reference herein.

Some examples are shown in Scheme 3. A variety of solvents can be usedfor this transformation, such as dichloromethane, methanol, ethanol,acetonitrile as well as water or aqueous mixtures. A variety of aminecomponents can be used in Step B, including primary or secondary amines,amino alcohols, hydrazine or hydroxylamine derivatives, amide orsulfonamide derivatives, as well as amino acids, amino esters, aminoamides or peptides. The organoboron compound in Step B can be a boronicacid or boronate, as well as a derivative of boronic acid with amines,diamines, amino alcohols or diols. By using chiral amines or chiralorganoboron derivatives the product of this process can be obtained withhigh stereochemical purity.

Step C involves the removal of one or both amine substituents in theamine component of Step B and may include the subsequent introduction ofother desired amine substituents using typical amine chemistry,including alkylation, reductive amination, amide or sulfonamide bondformation, etc. In this fashion, a wide range of amino amide derivativescan be formed. For example, as illustrated in Scheme 4, the use ofbenzyl or dibenzyl amines in Step B, can be followed by a de-benzylationstep of the resulting products, such as 28, involving catalytichydrogenation or other methods, leading to amine amides 29.Alternatively, benzhydryl amine adducts (e.g., by using4,4′-dimethoxybenzhydrylamine) such as 30, can produce 29 byacid-mediated removal of the benzhydryl group. The use of allyl ordiallylamines in Step B gives compounds such as 31, which can besubjected to known deallylation processes (e.g., Pd-catalysis)(Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem., 58:6109, 1993)either completely to form 29 or under milder conditions to givemono-deallylated products 32. This approach is more suitable for solidphase synthesis and combinatorial chemistry. A typical example is shownin Scheme 4. Finally, amino amides 29 can be further functionalized toform amino amides 33.

Peptides:

In another aspect, the present invention features methods of preparing apeptide of formula 10 or of formula 11. In Step A, an amino amidederivative 6 is converted to a glyoxamide intermediate 7 which isreacted in Step B with an amine 8 and an organoboron derivative 9 toform dipeptide 10. The use of a primary amine 8 having Rc=R⁶ and Rd=Hgives peptide 11. Alternatively, compound 11 is produced in Step C fromcompound 10 via the removal of one or both substituents Rc and Rd,followed by the incorporation of R⁶.

In these methods, R¹, R², R⁴ and R⁶ are independently selected from agroup consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl,acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino,sulfonylamino, and alkoxy. Rw can be hydrogen, alkyl, aryl orheteroaryl. In some embodiments, two or more of R¹, R², R⁴ and R⁶ can beconnected together forming one or more rings. R³ and R⁵ areindependently selected from a group consisting of alkyl, aryl,heteroaryl, allyl, alkenyl, alkynyl, and allenyl. Rc and Rd areindependently selected from a group consisting of hydrogen, alkyl,allyl, benzyl, aryl, heteroaryl, acyl, sulfonyl, amino, acylamino,sulfonylamino, and alkoxy. In some embodiments, Rc and Rd can be joinedtogether forming a ring. X and Y are independently selected from a groupconsisting of hydroxy, alkoxy, aryloxy, amino, alkylamino, ordialkylamino. In some embodiments, X and Y can be joined togetherforming a ring. In some embodiments, R¹, R², R³, R⁴, R⁵, Rc, Rd, Rw, Xor Y can also be connected to a polymeric chain or other solid phasematerial.

By combining the synthesis of an amino amide with its conversion to apeptide through the iterative use of Steps A-C, it is possible toproduce peptides of highly diverse structures, including theincorporation of unnatural amino acid units. Scheme 5 shows anillustrative example of the conversion of amine 34 to amino amides 35and 36, followed by the conversion of 36 to dipeptide 37 and 38.

Peptidomimetics:

In another aspect, the present invention features methods of preparing apeptidomimetic of formula 14. An amino amide (or peptide) derivative 6is reacted with a 1,2-dicarbonyl compound 13 and an organoboronderivative 12 to form peptidomimetic 14. An example is the conversion of38 to 39 (Scheme 5).

In these methods, R¹, R², and R⁴ are independently selected from a groupconsisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl,sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, andalkoxy. In some embodiments, two or more of R¹, R², R³ and R⁴ can beconnected together forming one or more rings. Rw can be hydrogen, alkyl,aryl or heteroaryl. R⁸ can be hydrogen, alkyl, alkenyl, aryl,heteroaryl, amino, alkylamino, dialkylamino, hydroxyamino, alkoxyamino,hydroxyl, alkoxy, aryloxy or heteroaryloxy. R³ and R⁷ are independentlyselected from a group consisting of alkyl, aryl, heteroaryl, allyl,alkenyl, alkynyl, and allenyl. X and Y are independently selected from agroup consisting of hydroxy, alkoxy, aryloxy, amino, alkylamino, anddialkylamino. In some embodiments, X and Y can also be joined togetherforming a ring. In some embodiments, R¹, R², R³, R⁴, R⁷, R⁸, Rw, X or Ycan also be connected to a polymeric chain or other solid phasematerial.

In another aspect, the present invention features methods of preparing apeptidomimetic of formula 17. An amino amide derivative 6 is convertedto a glyoxamide intermediate 7, which is reacted with and a organoboronderivative 15 and an amino carbonyl derivative 16 to form peptidomimetic17.

In these methods, R¹, R², R⁴, and R¹⁰ are independently selected from agroup consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl,acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino,sulfonylamino, and alkoxy. Rw can be hydrogen, alkyl, aryl orheteroaryl. In some embodiments, two or more of R¹, R², R³ and R⁴ can beconnected together forming one or more rings; two or more of R¹⁰, R¹¹and R¹² can also be connected together forming one or more rings. R³, R⁹and R¹¹ are independently selected from a group consisting of alkyl,aryl, heteroaryl, allyl, alkenyl, alkynyl, and allenyl. R¹² is hydrogen,alkyl, alkenyl, aryl, heteroaryl, amino, alkylamino, dialkylamino,hydroxyamino, alkoxyamino, hydroxyl, alkoxy, aryloxy or heteroaryloxy. Xand Y are independently selected from a group consisting of hydroxy,alkoxy, aryloxy, amino, alkylamino, and dialkylamino. In someembodiments, X and Y can also be joined together forming a ring. In someembodiments, R¹, R², R³, R⁴, R⁹, R¹⁰, R¹¹, R¹², Rw, or Y can also beconnected to a polymeric chain or other solid phase material.

Solid Phase Synthesis:

The methods of the present invention can be also performed in the solidphase by attaching one of the components on a solid support and by usingstandard solid phase techniques leading to amino amides, peptides orpeptidomimetics after the final cleavage from the solid support. Avariety of solid supports and linkers, followed by the appropriate finalcleavage procedures can be used for this purpose. Scheme 6 illustrates asolid phase synthesis of a complex amino amide. Rink amine resin 40, isconverted to aniline derivative 41 which, according to Step A, isconverted to glyoxamide 43 via the oxidation of intermediate glycolamide42. Performing Step B on 43, followed by cleavage from the resin givesthe amino amide product.

Combinatorial Libraries:

Since the process described in this invention involves a multicomponentreaction it allows the direct and rapid generation of combinatoriallibraries of the products, by varying the desired substituents. The term“combinatorial library” as used herein refers to a set of compounds thatare made by the same process, by varying one or more of the reagents.Combinatorial libraries may be made as mixtures of compounds, or asindividual pure compounds, generally depending on the methods used foridentifying active compounds. Where the active compound may be easilyidentified and distinguished from other compounds present by physicaland/or chemical characteristics, it may be preferred to provide thelibrary as a large mixture of compounds. Large combinatorial librariesmay also be prepared by massively parallel synthesis of individualcompounds, in which case compounds are typically identified by theirposition within an array. Intermediate between these two strategies is“deconvolution”, in which the library is prepared as a set of sub-pools,each having a known element and a random element. For example, using themethods of the invention each sub-pool might be prepared from only asingle amine (where each sub-pool contains a different amine), but amixture of different carbonyl derivatives (or organoboron reagents).When a sub-pool is identified as having activity, it is resynthesized asa set of individual compounds (each compound having been present in theoriginal active sub-pool), and tested again to identify the compoundsresponsible for the activity of the sub-pool.

Such libraries can be generated either in solution or in the solidphase, upon attachment of one substituent onto a solid support. Forexample, one may couple the starting amine component (e.g., 1, 6) to asubstrate through either R¹ or R², convert the amine to one or moreglyoxamides/ketoamides, and react the immobilized glyoxamide/ketoamidewith a mixture of different organoboron compounds and/or carbonylcompounds to produce a mixture of bound products. Alternatively, thecarbonyl compound may be immobilized, and a mixture of organoboroncompounds and/or glyoxamides/ketoamides added. Combinatorial librariesmay be generated either as individual compounds or as mixtures ofcompounds.

An illustrative example of a dipeptide having a natural and unnaturalamino acid unit is shown in Scheme 7. Beginning with sulfonamide resin46, the dipeptide 47 is generated, which upon cleavage under standardconditions gives the dipeptide derivative 48. Alternatively,deallylation of 48 gives 49, which can be used in another 3-componentprocess to give peptidomimetic 50. Conversion of 49 to glyoxamide 51followed by a 3-component process gives dipeptide 52. Furthermanipulations and/or cleavage from the resin leads to thefinal-products.

EXAMPLES

The invention will be further described in the following examples, whichare illustrative only, and which are not intended to limit the scope ofthe invention described in the claims.

In the following examples, efforts have been made to ensure accuracywith respect to numbers used (e.g., amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees centigrade,and pressure is at or near atmospheric. Starting materials used in theseexamples are generally either commercially available or can be readilyprepared from commercially available reagents by a procedure involvingone or more steps.

Example 1

N-Benzyl-3,3-dimethylacrylic amide (830 mg, 4.38 mmol) was dissolved inmethanol (15 mL) and cooled to −78° C. Ozone was bubble through thissolution until the blue color persisted. After flashing out excess O₃with O₂, excess dimethylsulfide was added to the solution. The reactionmixture was gradually warmed up to 0° C. for 1 h and further warmed upto room temperature for 1 h. After removal of volatiles, the residue waschromatographed with hexane-ethyl acetate (50:50) to yield the desiredproduct. The product showed satisfactory spectral data by H¹ NMR.

Example 2

Tartaric acid (694 mg, 4.62 mmol) in DMF (20 mL) was added tobenzylamine (1.0 mL, 9.06 mmol), followed by Et₃N (1.27 mL, 9.11 mmol),HOBT (1.225 g, 9.06 mmol), and EDC•HCl (1.773 g, 9.06 mmol). The mixturewas stirred at room temperature overnight. Saturated NaHCO₃ was added toquench the reaction. The white precipitate was filtered and washed withsaturated NaHCO₃, EtOAc and Et₂O, dried under vacuum (1.275 g, 86%yield). The resulting N,N′-Dibenzyl-2,3-dihydroxy-succinamide (328 mg,1.0 mmol) was suspended in 10% MeOH in DCM (5 mL), and H₅IO₆ (230 mg,1.0 mmol) was added. The reaction mixture was stirred at roomtemperature for 1 h. The white solid was filtered and washed with DCM.To the filtered organic solution was added H₂O, after separation theorganic layer, the aqueous layer was extracted with DCM several times.The combined organic layer was then dried over MgSO₄, and evaporated toget crude product without further purification.

Example 3

To a solution of N-benzyl glyoxyamide (prepared according to Example 1or 2) in acetonitrile, was added dibenzylamine (1.05 equivalent) and2-thiopheneboronic acid (1.05 equivalent), and the reaction mixture wasrefluxed overnight. After it was diluted with EtOAc, the mixture waswashed with 0.1N NaOH, brine, and dried over MgSO₄. The residue waspurified by flash chromatography giving the product in 55% yield. ¹H NMR(360 MHz, CDCl₃) δ 7.42-7.16 (m, 16H), 7.05 (dd, J=5.1, 3.5 Hz, 1H)7.02-6.99 (m, 1H), 4.69 (s, 1H), 4.60-4.40 (m, 2H), 3.80 (d, J=13.6 Hz,2H), 3.39 (d, J=13.6 Hz, 2H); ¹³C NMR (63 MHz, CDCl₃) δ 170.2, 138.4,138.1, 135.8, 128.7, 128.6, 128.6, 127.8, 127.6, 127.4, 126.4, 125.8,62.6, 54.6, 43.6.

Example 4

Prepared similarly to Example 3 in 70% yield. ¹H NMR (250 MHz, CDCl₃) δ7.71-6.93 (m, 20H), 6.51 (d, J=15.9 Hz, 1H), 6.36 (dd, J=15.9, 8.9 Hz,1H), 4.59-4.33 (m, 2H), 3.87 (d, J=8.9 Hz, 1H), 3.81 (d, J=13.5 Hz, 2H),3.31 (d, J=13.5 Hz, 2H); ¹³C NMR (63 MHz, CDCl₃) δ 171.9, 138.5, 138.3,137.1, 136.4, 128.8, 128.7, 128.6, 128.5, 128.0, 127.7, 127.5, 127.4,126.7, 122.2, 65.7, 54.7, 43.4.

Example 5

Prepared similarly to Example 3 in 91% yield. ¹H NMR (360 MHz, CDCl₃) δ7.45-6.87 (m, 20H), 6.47 (d, J=15.6 Hz, 1H), 6.17 (dd, J=15.6, 7.6 Hz,1H), 4.84 (s, 1H), 4.52-4.32 (m, 2H), 3.80 (d, J=7.6 Hz, 1H); ¹³C NMR(63 MHz, CDCl₃) δ 171.7, 142.8, 142.6, 138.1, 136.1, 133.3, 128.5,128.4, 127.8, 127.5, 127.3, 127.2, 126.5, 126.4, 64.4, 62.6, 43.1.

Example 6

Prepared similarly to Example 3 in 67% yield. ¹H NMR (360 MHz, CDCl₃) δ7.54-7.06 (m, 15H), 6.60 (d, J=15.7 Hz, 1H), 6.18 (dd, J=15.7, 7.6 Hz,1H), 4.51-4.33 (m, 2H), 3.89 (d, J=7.6 Hz, 1H), 3.81-3.67 (m, 2H); ¹³CNMR (90 MHz, CDCl₃) δ 171.6, 139.1, 138.2, 136.1, 133.1, 128.5, 128.4,128.0, 127.8, 127.5, 127.3, 127.1, 126.6, 126.4, 64.6, 51.8, 43.1.

Example 7

Prepared similarly to Example 3 in 55% yield. ¹H NMR (360 MHz, CDCl₃) δ7.58-7.10 (m, 10H), 6.49 (d, J=15.4 Hz, 1H), 6.18 (dd, J=15.4, 9.1 Hz,1H), 5.78-5.60 (m, 2H), 5.18-5.03 (m, 4H), 4.53-4.30 (m, 2H), 3.94 (d,J=9.1 Hz, 1H), 3.27-3.15 (m, 2H), 2.99-2.88 (m, 2H); ¹³C NMR (90 MHz,CDCl₃) δ 171.9, 138.3, 136.3, 136.2, 134.9, 128.5, 128.3, 127.7, 127.5,127.2, 126.4, 122.7, 118.0, 66.7, 53.4, 43.1.

Example 8

Prepared similarly to Example 3 in 42% yield. ¹H NMR (360 MHz, CDCl₃) δ7.68-7.06 (m, 9H), 5.88-5.63 (m, 2H), 5.15-5.05 (m, 4H), 4.93 (s, 1H),4.55-4.39 (m, 2H), 3.29-3.07 (m, 4H); ¹³C NMR (90 MHz, CDCl₃) δ 171.1,138.1, 136.0, 134.5, 133.2, 130.6, 129.3, 128.5, 127.6, 127.3, 127.2,125.9, 117.9, 68.6, 53.2, 43.2.

Example 9

Prepared similarly to Example 3 in 57% yield. ¹H NMR (250 MHz, CDCl₃) δ8.35-8.21 (m, 1H), 7.90-7.73 (m, 2H), 7.63-7.11 (m, 9H), 5.86-5.65 (m,2H), 5.19 (s, 1H), 5.17-5.00 (m, 4H), 4.56-4.32 (m, 2H), 3.39-3.08 (m,4H); ¹³C NMR (63 MHz, CDCl₃) δ 172.0, 138.2, 134.9, 134.0, 132.7, 132.5,128.7, 128.6, 128.5, 127.6, 127.3, 127.0, 126.2, 125.6, 125.0, 124.0,118.0, 65.9, 53.4, 43.2.

Example 10

The product of Example 9 (95 mg, 0.26 mmol) was placed in a 10 mL vacuumdried flask containing, Pd(PPh₃)₄ (6 mg), and N,N-dimethyl barbituricacid (243 mg, 1.54 mmol). Dichloromethane (1.5 mL) was added and thereaction mixture was refluxed for 6 h. A large amount of EtOAc wasadded, washed with aqueous Na₂CO₃ several times. The organic layer wasdried over MgSO₄. After the removal of volatiles, the residue was flashchromotographied with 2% MeOH in DCM to obtain product (74 mg, 99%yield). ¹H NMR (360 MHz, CDCl₃) δ 8.20-7.04 (m, 13H), 5.08 (s, 1H),4.48-4.29 (m, 2H); ¹³C NMR (90 MHz, CDCl₃) δ 173.2, 138.2, 134.0, 131.9,131.8, 128.8, 128.5, 128.4, 127.6, 127.2, 126.4, 125.7, 125.3, 125.1,123.4, 56.6, 43.1.

Example 11

Prepared similarly to Example 3 in 67% yield. ¹H NMR (360 MHz, CDCl₃) δ7.40-7.03 (m, 20H), 6.40 (d, J=16.3 Hz, 1H), 6.24 (dd, J=16.3, 9.3 Hz,1H), 3.75-3.57 (m, 5H), 3.52-3.40 (m, 1H), 3.32 (d, J=13.7 Hz, 2H),2.86-2.66 (m, 2H); ¹³C NMR (63 MHz, CDCl₃) δ 171.6, 138.5, 138.3, 136.6,136.1, 128.5, 128.4, 128.3, 128.2, 128.1, 127.8, 127.6, 127.0, 126.6,126.4, 126.4, 65.5, 54.3, 52.8, 39.7, 35.2.

Example 12

To the solution of the product of Example 11 (451 mg, 0.98 mmol) inEtOAc-MeOH 1:1 (20 mL) was added 5% wt Pd/C (266 mg). The reactionmixture was stirred under the atmosphere of hydrogen gas until all thestarting material was consumed, then filtered through celite pad andvolatiles were removed. Pure product was isolated by flashchromatography using 10% MeOH in DCM as an eluent (174 mg, 63% yield).¹H NMR (250 MHz, CDCl₃) δ 7.67-7.07 (m, 10H), 3.54 (dd, J=13.3, 7.0 Hz,2H), 3.42-3.27 (m, 1H), 2.84 (t, J=7.0 Hz, 2H), 2.76-2.63 (m, 2H),2.28-2.07 (m, 1H) 1.90-1.67 (m, 3H); ¹³C NMR (90 MHz, CDCl₃) δ 174.5,141.0, 138.8, 128.5, 128.4, 128.3, 128.2, 126.2, 125.8, 54.5, 40.0,36.4, 35.6, 31.8.

Example 13

Prepared similar to Example 2 from the product of Example 12 in 76%yield. ¹H NMR (360 MHz, MeOD-d₄) δ 7.39-6.93 (m, 20H), 4.56-4.47 (m,2H), 4.44-4.33 (m, 2H), 3.56-3.27 (m, 4H), 2.88-2.74 (m, 4H), 2.72-2.49(m, 4H), 2.24-1.81 (m, 4H); ¹³C NMR (90 MHz, MeOD-d₄) δ 174.6, 174.3,174.2, 173.9, 142.5, 142.2, 140.3, 129.8, 129.5, 129.5, 129.4, 127.4,127.1, 127.0, 74.7, 74.2, 54.2, 54.0, 42.0, 41.9, 36.4, 36.3, 35.9,35.9, 35.0, 32.9, 32.7.

Example 14

The product of Example 13 was converted to the corresponding glyoxamidesimilarly to Example 2, and reacted with p-methoxyphenyl boronic acidand dibenzylamine, similarly to Example 3. The dipeptide product wasobtained in 74% overall yield, containing a mixture of twodiastereomers. ¹H NMR (250 MHz, CDCl₃) δ 8.40-8.08 (m, 1H), 7.56-6.72(m, 25H), 4.71-4.55 (m, 1H), 4.40 (s, 1H), 3.91-3.76 (m, 2H), 3.75 (s,3H), 3.58-3.13 (m, 4H), 2.70-2.43 (m, 4H), 2.25-1.83 (m, 2H); ¹³C NMR(63 MHz, CDCl₃) δ 171.6, 171.5, 171.0, 170.9, 159.1, 140.9, 138.7,138.2, 138.1, 131.6, 131.5, 129.0, 128.6, 128.5, 128.2, 128.1, 127.3,126.1, 125.8, 125.2, 125.1, 113.4, 66.9, 66.9, 55.0, 54.5, 54.4, 52.6,52.5, 40.5, 40.5, 35.3, 35.2, 34.8, 31.6, 31.2.

Example 15

Prepared from the product of Example 14 similarly to Example 12 in 56%yield containing two diastereomers. Diatereomer A: ¹H NMR (360 MHz,MeOD-d₄) δ 7.51-6.73 (m, 14H), 4.46 (s, 1H), 4.28 (dd, J=8.3, 5.4 Hz,1H), 3.73 (s, 3H), 3.42-3.24 (m, 2H), 2.67 (t, J=7.4 Hz, 2H), 2.63-2.43(m, 2H), 2.08-1.79 (m, 2H); ¹³C NMR (90 MHz, MeOD-d₄) δ 175.8, 173.6,160.9, 142.3, 140.2, 134.2, 129.8, 129.6, 129.5, 129.4, 129.1, 127.4,127.0, 115.1, 59.7, 55.7, 54.2, 41.8, 36.3, 35.2, 32.9; Diastereomer B:¹H NMR (360 MHz, MeOD-d₄) δ 7.52-6.72 (m, 14H), 4.48 (s, 1H), 4.18 (dd,J=9.5, 4.6 Hz, 1H), 3.72 (s, 3H), 3.48-3.31 (m, 2H), 2.76 (t, J=7.3 Hz,2H), 2.46-2.25 (m, 2H), 2.04-1.71 (m, 2H); ¹³C NMR (63 MHz, MeOD-d₄) δ175.8, 173.9, 160.9, 142.0, 140.3, 134.3, 129.8, 129.5, 129.4, 129.3,129.2, 127.3, 127.0, 115.1, 59.4, 55.7, 54.1, 41.9, 36.4, 35.0, 32.7.

Example 16

One of the diastereomers of Example 15 (47 mg, 0.10 mmol) was dissolvedin a mixture of DCM and MeOH (1:1, 3 mL), and mixed with glyoxylic acidmonohydrate (11 mg, 0.12 mmol), followed by the addition 2-furanboronicacid (13 mg, 0.12 mmol). The reaction mixture was stirred at roomtemperature for 22 h. After removal of the volatiles, the crude productwas purified by EtOAc:MeOH:NH₄OH (8:2:0.5) as eluent (47 mg, 76% yield)containing two diastereomers. ¹H NMR (360 MHz, MeOD-d₄) δ 7.56-6.73 (m,15H), 6.47-6.24 (m, 2H), 4.54 (s, 0.4H), 4.46 (s, 0.6H), 4.38 (s, 0.4H),4.31 (s, 0.6H), 4.23-4.14 (m, 1H), 3.75 (s, 1.8H), 3.74 (s, 1.2H),3.48-3.31 (m, 2H), 2.82-2.66 (m, 2H), 2.51-2.26 (m, 2H), 2.05-1.71 (m,2H); ¹³C NMR (90 MHz, MeOD-d₄) δ 174.3, 173.9, 173.8, 173.8, 173.2,173.0, 161.6, 152.7, 143.8, 142.0, 140.3, 130.5, 129.8, 129.5, 129.4,129.4, 127.3, 127.0, 64.8, 64.3, 60.3, 60.1, 55.8, 54.2, 42.0, 36.2,35.0, 32.8, 32.7.

Example 16

Part 1: To a mixture of Rink amine resin (503 mg, 0.10 mmol) in DMF (4mL) was added N-Fmoc-4-aminobenzoic acid (111 mg, 0.30 mmol), DIC(N,N′-diisopropylcarbodiimide) (48 μL, 0.30 mmol), and HOBT(1-hydroxybenzo-triazole) (41 mg, 0.30 mmol). The mixture was stirred atroom temperature overnight under argon. The resin was filtered off andwashed repeated with DMF, MeOH and DCM. The resin was then treated with20% piperidine in DMF for half an hour, filtered off and washed repeatlywith DMF, MeOH and DCM, dried under vacuum.

Part 2: The resin from Step 1 was swelled in DMF (4 mL) and reacted withacetoxyacetic acid (36 mg, 0.30 mmol), DIC (48 mL, 0.30 mmol), and HOBT(41 mg, 0.30 mmol). The mixture was stirred for 16 h. The resin wasfiltered off and washed repeatly with DMF, MeOH and DCM. To the acylatedresin in DMF (3 mL) and MeOH (1.5 mL) was added K₂CO₃ (139 mg, 1.0mmol), and the mixture was stirred at room temperature for 22 h. Theresin was filtered off and washed repeatly with H₂O, MeOH and DCM, driedunder vacuum.

Part 3: To the solution of oxalyl chloride (27 mL, 0.30 mmol) in DCM (1mL) was added dimethyl sulfoxide (43 mL, 0.60 mmol) at −78° C., and themixture was stirred for 30 min. To this solution was added theglycolamide resin from Part 2 diluted with DCM (2 mL). The mixture wasstirred at −78° C. for 1 h, and reacted with Et₃N (0.11 mL, 0.77 mmol)and allowed to warm up to room temperature for 2 h. The resin wasfiltered off, washed with DCM.

Part 4: Acetonitrile (4 mL) was added to the resin from Part 4, followedby the addition of dibenzylamine (45 mL, 0.23 mmol), and(E)-styrylboronic acid (34 mg, 0.23 mmol). The mixture was refluxed for17 h. After cooling to room temperature, the resin was filtered off,washed with MeOH, DCM, and then cleaved with 15% TFA in DCM for 1 h. Theresin was filtered off and washed with MeOH, DCM. The solution wasevaporated (co-evaporate with toluene). The residue was dissolved inDCM, neutralized with Et₃N, and evaporated. The crude mixture waspurified by flash chromatography with gradient mixture of MeOH and DCMgiving the product (12 mg, 25% yield from the initial loading). ¹H NMR(500 MHz, MeOD-d₄) δ 7.86 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H),7.50-7.21 (m, 15H), 6.64 (d, J=16.0 Hz, 1H), 6.46 (dd, J=16.0, 8.4 Hz,1H), 4.06 (d, J=8.4 Hz, 1H), 3.92 (d, J=13.6 Hz, 2H), 3.72 (d, J=13.6Hz, 2H), ¹³C NMR (125 MHz, MeOD-d₄) δ 171.3, 171.7, 142.5, 140.2, 137.8,137.7, 130.3, 130.1, 129.8, 129.7, 129.6, 129.1, 128.4, 127.7, 124.5,120.3, 68.8, 56.3.

Example 17

Part 1: To 4-sulfamylbutyryl AM resin (134 mg, 0.15 mmol) were addedCHCl₃ (1.7 mL), iPr₂NEt (131 μL, 0.75 mmol), and Fmoc-Phe-OH (178 mg,0.45 mmol). The mixture was stirred for 10 min followed by cooling to−20° C. After 20 min, PyBOP (234 mg, 0.45 mmol) was added to thereaction mixture and stirred for 8 h. The resin was filtered, washedwith MeOH, DCM, DMF, and treated with 20% piperidine in DMF (3 mL) for30 min, The resin was filtered off, washed with DMF, DCM, and driedunder vacuum.

Part 2: The resin from Part 1 was swelled in NMP (2 mL) and mixed with2,3-dihydroxy-3-phenyl-propionic acid (82 mg, 0.45 mmol), iPr₂NEt (131μL, 0.75 mmol), and PyBOP (234 mg, 0.45 mmol). After stirring at roomtemperature for 8 h, the resin was filtered off, washed with NMP, MeOH,DCM, and dried under vacuum.

Part 3: The resin from Part 2 (71 mg, 0.059 mmol) was swelled in 10%MeOH in DCM (2 mL), and reacted with H₅₁O₆ (20 mg, 0.087 mmol). Themixture was stirred for 1 h, and the resin was filtered off, and washedwith MeOH and DCM.

Part 4: To the resin from Part 3 were added toluene (1.0 mL),acetonitrile (0.5 mL), diallylamine (25 μL, 0.20 mmol),(E)-styrylboronic acid (30 mg, 0.2 mmol). The reaction mixture wasstirred at 55° C. overnight. The resin was filtered off, washed withMeOH, DCM, and dried under vacuum.

Part 5: To the resin from Part 4 were added NMP (1 mL), iPr₂NEt (59 μL,0.34 mmol), and iodoacetonitrile (101 μL, 1.36 mmol). The reactionmixture was shielded from light, stirred for 24 h, filtered off, andwashed with NMP, DCM and THF. To the resulting resin were added THF (1mL) and benzylamine (7.5 μL, 0.068 mmol). The mixture was stirred for 4h. The resin was filtered off and washed with MeOH, DCM. The organicsolution was evaporated and the residue was purified with 30% EtOAc inhexane to obtain desired product (4 mg, 14% yield calculated fromtheoretical loading of the initial resin). ¹H NMR (500 MHz, CDCl₃) δ7.79-7.71 (m, 1H), 7.40-7.04 (m, 16H), 6.48 (d, J=16.0 Hz, 1H), 6.04(dd, J=16.0, 9.3 Hz, 1H), 5.78-5.60 (m, 2H), 5.25-5.06 (m, 4H), 4.68(dd, J=15.5, 7.5 Hz, 1H), 4.42-4.28 (m, 2H), 3.89 (d, J=8.8 Hz, 1H),3.24-3.06 (m, 4H), 2.90 (dd, J=13.9, 7.4 Hz, 2H), ¹³C NMR (125 MHz,CDCl₃) δ 172.7, 170.6, 136.5, 135.1, 129.3, 129.2, 128.7, 128.6, 128.5,127.9, 127.6, 127.4, 127.0, 126.6, 122.4, 118.2, 67.0, 54.3, 53.6, 43.5,37.8

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. A method for preparing an amino amide, the method comprising:providing an amine derivative of formula 1

wherein: R¹ and R² are independently selected from the group consistingof hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl,amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy,provided that R¹ and R² can be connected together forming a ring;converting amine derivative 1 to a compound of formula 2

wherein: Rw is hydrogen, alkyl, aryl, or heteroaryl; contacting thecompound of formula 2 with an amine derivative of formula 3 and anorganoboron compound of formula 4 to form a reaction mixture

wherein: R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, orallenyl; Ra and Rb are independently selected from the group consistingof hydrogen, alkyl, allyl, benzyl, aryl, heteroaryl, acyl, sulfonyl,amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy,provided that Ra and Rb can be joined together forming a ring; and X andY are independently selected from the group consisting of hydroxy,alkoxy, aryloxy, amino, alkylamino, and dialkylamino, provided that Xand Y can be joined together forming a ring; and allowing the reactionmixture to react to form an amino amide of formula 5


2. The method of claim 1, further comprising: converting the amino amideof formula 5 to an amino amide of formula 6

wherein: R⁴ is hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl,sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, oralkoxy.
 3. The method of claim 1, wherein one of R¹, R², R³, Ra, Rb, Rw,X and Y is connected to a polymeric chain or other solid phase material.4. The method of claim 1, wherein the amino amide of formula 5 is formedas a member of a combinatorial library.
 5. The method of claim 3,wherein the amino amide of formula 5 is formed as a member of acombinatorial library. 6-10. (canceled)
 11. A method for preparing apeptidomimetic compound, the method comprising: providing an amino amideor peptide derivative of formula 6

wherein: R¹, R², and R⁴ are independently selected from the groupconsisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl,sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, andalkoxy; and R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, orallenyl, provided that R¹, R², R³ and R⁴ can be connected togetherforming one or more rings; contacting the amino amide or peptidederivative of formula 6 with a 1,2 dicarbonyl compound of formula 13 andan organoboron compound of formula 12 to form a reaction mixture

wherein: Rw is hydrogen, alkyl, aryl or heteroaryl; R⁷ is alkyl, aryl,heteroaryl, allyl, alkenyl, alkynyl, or allenyl; R⁸ is hydrogen, alkyl,alkenyl, aryl, heteroaryl, amino, alkylamino, dialkylamino,hydroxyamino, alkoxyamino, hydroxyl, alkoxy, aryloxy or heteroaryloxy; Xand Y are independently selected from the group consisting of hydroxy,alkoxy, aryloxy, amino, alkylamino, and dialkylamino, provided that Xand Y can be joined together forming a ring; and allowing the reactionmixture to react to form a compound of formula 14


12. The method of claim 11, wherein one of R¹, R², R³, R⁴, R⁷, R⁸, Rw, Xor Y is connected to a polymeric chain or other solid phase material.13. The method of claim 11, wherein the compound of formula 14 is formedas a member of a combinatorial library.
 14. The method of claim 12,wherein the compound of formula 14 is formed as a member of acombinatorial library.
 15. A method for preparing a peptidomimeticcompound, the method comprising: providing an amino amide or peptidederivative of formula 6

wherein: R¹, R², and R⁴ are independently selected from the groupconsisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl,sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, andalkoxy; and R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, orallenyl, provided that R¹, R², R³ and R⁴ can be connected togetherforming one or more rings; converting the amino amide or peptidederivative of formula 6 to a compound of formula

wherein: Rw is hydrogen, alkyl, aryl or heteroaryl; contacting thecompound of formula 7 with an amino carbonyl compound of formula 16 andan organoboron compound of formula 15 to form a reaction mixture

wherein: R⁹ and R¹¹ are independently selected from the group consistingof alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, and allenyl; R¹⁰ ishydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl,amino, alkylamino, di alkyl amino, acylamino, sulfonyl amino, or alkoxy;R¹² is selected from the group consting of hydrogen, alkyl, alkenyl,aryl, heteroaryl, amino, alkylamino, dialkylamino, hydroxyamino,alkoxyamino, hydroxyl, alkoxy, aryloxy and heteroaryloxy, provided thatR¹⁰, R¹¹ and R¹² can be connected together forming one or more rings; Xand Y are independently selected from the group consisting of hydroxy,alkoxy, aryloxy, amino, alkylamino, and dialkylamino; X and Y can alsobe joined together forming a ring; and allowing the reaction mixture toreact to form a compound of formula 17


16. The method of claim 15, wherein one of R¹⁷, R², R³, R⁴, R⁹, R¹⁰,R¹¹, R¹², Rw, X or Y is connected to a polymeric chain or other solidphase material.
 17. The method of claim 15, wherein the compound offormula 17 is formed as a member of a combinatorial library.
 18. Themethod of claim 16, wherein the compound of formula 17 is formed as amember of a combinatorial library.
 19. A method for preparing acombinatorial library including a plurality of compounds, the methodcomprising: providing one or more amine derivatives of formula 1

wherein: R¹ and R² are independently selected from the group consistingof hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl,amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy,provided that R¹ and R² can be connected together forming a ring;converting the one or more amine derivatives 1 to compounds of formula 2

wherein: Rw is hydrogen, alkyl, aryl, or heteroaryl; contacting thecompounds of formula 2 with one or more amine derivatives of formula 3and organoboron compounds of formula 4 to form one or more reactionmixtures

wherein: R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, orallenyl; Ra and Rb are independently selected from the group consistingof hydrogen, alkyl, allyl, benzyl, aryl, heteroaryl, acyl, sulfonyl,amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy,provided that Ra and Rb can be joined together forming a ring; and X andY are independently selected from the group consisting of hydroxy,alkoxy, aryloxy, amino, alkylamino, and dialkylamino, provided that Xand Y can be joined together forming a ring; and allowing the reactionmixtures to react to form a combinatorial library including one or moreamino amides of formula 5


20. A method of preparing a combinatorial library including a pluralityof compounds, the method comprising: providing one or more amino amidederivatives of formula 6

wherein: R¹, R² and R⁴ are independently selected from the groupconsisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl,sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, andalkoxy, provided that two or more of R¹, R² and R⁴ can be connectedtogether forming one or more rings; R³ is alkyl, aryl, heteroaryl,allyl, alkenyl, alkynyl or allenyl; and Rw is hydrogen, alkyl, aryl, orheteroaryl; converting the amino amide derivatives of formula 6 to oneor more compounds of formula 7

wherein: Rw′ is hydrogen, alkyl, aryl, or heteroaryl; contacting thecompounds of formula 7 with one or more amines of formula 8 andorganoboron compounds of formula 9 to form one or more reaction mixtures

wherein: R⁵ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, orallenyl; Rc and Rd are independently selected from the group consistingof hydrogen, alkyl, allyl, benzyl, aryl, heteroaryl, acyl, sulfonyl,amino, acylamino, sulfonylamino, and alkoxy, provided that Rc and Rd canbe joined together forming a ring; and X and Y are independentlyselected from the group consisting of hydroxy, alkoxy, aryloxy, amino,alkylamino, and dialkylamino, provided that X and Y can also be joinedtogether forming a ring; and allowing the reaction mixtures to react toform one or more peptides of formula 10


21. A method of preparing a combinatorial library including a pluralityof compounds, the method comprising: providing one or more amino amidesor peptide derivatives of formula 6

wherein: R¹, R², and R⁴ are independently selected from the groupconsisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl,sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, andalkoxy; and R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, orallenyl, provided that R¹, R², R³ and R⁴ can be connected togetherforming one or more rings; contacting the amino amides or peptidederivatives of formula 6 with one or more 1,2 dicarbonyl compounds offormula 13 and organoboron compounds of formula 12 to form one or morereaction mixtures

wherein: Rw is hydrogen, alkyl, aryl or heteroaryl; R⁷ is alkyl, aryl,heteroaryl, allyl, alkenyl, alkynyl, or allenyl; R⁸ is hydrogen, alkyl,alkenyl, aryl, heteroaryl, amino, alkylamino, dialkylamino,hydroxyamino, alkoxyamino, hydroxyl, alkoxy, aryloxy or heteroaryloxy; Xand Y are independently selected from the group consisting of hydroxy,alkoxy, aryloxy, amino, alkylamino, and dialkylamino, provided that Xand Y can be joined together forming a ring; and allowing the reactionmixtures to react to form one or more compounds of formula 14


22. A method of preparing a combinatorial library including a pluralityof compounds, the method comprising: providing one or more amino amidesor peptide derivatives of formula 6

wherein: R¹, R², and R⁴ are independently selected from the groupconsisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl,sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, andalkoxy; and R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, orallenyl, provided that R¹; R², R³ and R⁴ can be connected togetherforming one or more rings; converting the amino amides or peptidederivatives of formula 6 to one or more compounds of formula 7

wherein: Rw is hydrogen, alkyl, aryl or heteroaryl; contacting thecompounds of formula 7 with one or more amino carbonyl compounds offormula 16 and organoboron compounds of formula 15 to form one or morereaction mixtures

wherein: R⁹ and R¹¹ are independently selected from the group consistingof alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, and allenyl; R¹⁰ ishydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl,amino, alkylamino, dialkylamino, acylamino, sulfonylamino, or alkoxy;R¹² is selected from the group consting of: hydrogen, alkyl, alkenyl,aryl, heteroaryl, amino, alkylamino, dialkylamino, hydroxyamino,alkoxyamino, hydroxyl, alkoxy, aryloxy or heteroaryloxy, provided thatR¹⁰, R¹¹ and R¹² can be connected together forming one or more rings; Xand Y are independently selected from the group consisting of: hydroxy,alkoxy, aryloxy, amino, alkylamino, or dialkylamino; X and Y can also bejoined together forming a ring; and allowing the reaction mixtures toreact to form one or more compounds of formula 17


23. A combinatorial library including a plurality of compounds, one ormore of the plurality of compounds in the combinatorial library beingprepared by the process of claim
 1. 24. A combinatorial libraryincluding a plurality of compounds, one or more of the plurality ofcompounds in the combinatorial library being prepared by a processcomprising: providing an amino amide derivative of formula 6

wherein: R¹, R² and R⁴ are independently selected from the groupconsisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl,sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, andalkoxy, provided that two or more of R¹, R² and R⁴ can be connectedtogether forming one or more rings; R³ is alkyl, aryl, heteroaryl,allyl, alkenyl, alkynyl or allenyl; and Rw is hydrogen, alkyl, aryl, orheteroaryl; converting the amino amide derivative of formula 6 to acompound of formula 7

wherein: Rw′ is hydrogen, alkyl, aryl, or heteroaryl; contacting thecompound of formula 7 with an amine of formula 8 and an organoboroncompound of formula 9 to form a reaction mixture

wherein: R⁵ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, orallenyl; Rc and Rd are independently selected from a group consisting ofhydrogen, alkyl, allyl, benzyl, aryl, heteroaryl, acyl, sulfonyl, amino,acylamino, sulfonylamino, and alkoxy, provided that Rc and Rd can bejoined together forming a ring, and X and Y are independently selectedfrom a group consisting of hydroxy, alkoxy, aryloxy, amino, alkylamino,and dialkylamino, provided that X and Y can also be joined togetherforming a ring, and allowing the reaction mixture to react to form apeptide of formula 10


25. A combinatorial library including a plurality of compounds, one ormore of the plurality of compounds in the combinatorial library beingprepared by the process of claim
 11. 26. A combinatorial libraryincluding a plurality of compounds, one or more of the plurality ofcompounds in the combinatorial library being prepared by the process ofclaim
 15. 27. The method of claim 1, wherein Rw is hydrogen. 28.(canceled)
 29. The method of claim 11, wherein Rw is hydrogen.
 30. Themethod of claim 15, wherein Rw is hydrogen.